Renal epithelial injury and fibrosis.

Chronic kidney disease at a certain advanced stage inevitably progresses to end stage renal failure characterized by the progressing loss of nephrons accompanied by the increasing appearance of fibrotic tissue, called renal fibrosis. The urgent question is whether renal fibrosis is a response to injury or if fibrosis acquires a self-sustaining progressive potential that actively contributes to the deterioration of the kidney. The present review distinguishes between renal fibrosis subsequent to a glomerular injury and fibrosis subsequent to a primary tubular injury. Glomerular diseases enter a progressing course after encroaching onto the tubule leading to what is generally called "tubulointerstitial fibrosis". The progression of the injury at the level of the tubulointerstitium appears to be fully dependent on the progression of the disease in the corresponding glomerulus. Primary tubular injuries have a very good chance of recovery. If they develop a local fibrotic process, this seems to be supportive for recovery. Cases in which recovery fails appear to secondarily initiate a glomerular disease accounting for a glomerulus-dependent vicious cycle to progression. Even if most researchers think of renal fibrosis as a process promoting the progression of the disease this review points out that the available structural evidence speaks in favour of a protective role of fibrosis supporting recovery after acute tubular injury or, under progressing circumstances, providing a firm three-dimensional framework that permits still intact or partially damaged nephrons to survive. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.

The podocyte's response to stress: the enigma of foot process effacement.

Progressive loss of podocytes is the most frequent cause accounting for end-stage renal failure. Podocytes are complex, terminally differentiated cells incapable of replicating. Thus lost podocytes cannot be replaced by proliferation of neighboring undamaged cells. Moreover, podocytes occupy a unique position as epithelial cells, adhering to the glomerular basement membrane (GBM) only by their processes, whereas their cell bodies float within the filtrate in Bowman's space. This exposes podocytes to the danger of being lost by detachment as viable cells from the GBM. Indeed, podocytes are continually excreted as viable cells in the urine, and the rate of excretion dramatically increases in glomerular diseases. Given this situation, it is likely that evolution has developed particular mechanisms whereby podocytes resist cell detachment. Podocytes respond to stress and injury by undergoing tremendous changes in shape. Foot process effacement is the most prominent and, yet in some ways, the most enigmatic of those changes. This review summarizes the various structural responses of podocytes to injury, focusing on foot process effacement and detachment. We raise the hypothesis that foot process effacement represents a protective response of podocytes to escape detachment from the GBM.

Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells.

We recently showed in a tetracycline-controlled transgenic mouse model that overexpression of transforming growth factor (TGF)-beta1 in renal tubules induces widespread peritubular fibrosis and focal degeneration of nephrons. In the present study we have analyzed the mechanisms underlying these phenomena. The initial response to tubular cell-derived TGF-beta1 consisted of a robust proliferation of peritubular cells and deposition of collagen. On sustained expression, nephrons degenerated in a focal pattern. This process started with tubular dedifferentiation and proceeded to total decomposition of tubular cells by autophagy. The final outcome was empty collapsed remnants of tubular basement membrane embedded into a dense collagenous fibrous tissue. The corresponding glomeruli survived as atubular remnants. Thus, TGF-beta1 driven autophagy may represent a novel mechanism of tubular decomposition. The fibrosis seen in between intact tubules and in areas of tubular decomposition resulted from myofibroblasts that were derived from local fibroblasts. No evidence was found for a transition of tubular cells into myofibroblasts. Neither tracing of injured tubules in electron micrographs nor genetic tagging of tubular epithelial cells revealed cells transgressing the tubular basement membrane. In conclusion, overexpression of TGF-beta1 in renal tubules in vivo induces interstitial proliferation, tubular autophagy, and fibrosis, but not epithelial-to-mesenchymal transition.

New insights into structural patterns encountered in glomerulosclerosis.

PURPOSE OF REVIEW: The term 'focal segmental glomerulosclerosis' covers a variety of diseases with different histopathological patterns. There is a need for clues to interpret histological findings in terms of etiology. Studies in transgenic animal models published in recent years have targeted the podocyte with respect to its impact on the development of glomerulosclerosis. Our aim was to survey those models in an attempt to discover correlations between histopathological patterns and pathogenic mechanisms. RECENT FINDINGS: The most obvious conclusion to draw from recent studies is that virtually all forms of glomerulosclerosis start with a lesion or dysfunction of podocytes. In hereditary glomerular diseases and transgenic animal models, two patterns of glomerular degeneration may be distinguished. All diseases with late onset appear to follow the 'classic' pathway to focal segmental glomerulosclerosis, starting with an adhesion of the tuft to the Bowman's capsule and eventually leading to nephron degeneration. In contrast, those with early onset frequently exhibit changes that indicate a severe dysregulation of podocyte function resulting in diffuse global endocapillary damage (i.e. mesangial expansion and rarefaction of capillaries). SUMMARY: Such insights derived from animal models might be useful in elucidating the mechanisms of multifactorial human diseases like diabetic glomerulopathy.

Pathways to nephron loss starting from glomerular diseases-insights from animal models.

Studies of glomerular diseases in animal models show that progression toward nephron loss starts with extracapillary lesions, whereby podocytes play the central role. If injuries remain bound within the endocapillary compartment, they will undergo recovery or be repaired by scaring. Degenerative, inflammatory and dysregulative mechanisms leading to nephron loss are distinguished. In addition to several other unique features, the dysregulative mechanisms leading to collapsing glomerulopathy are particular in that glomeruli and tubules are affected in parallel. In contrast, in degenerative and inflammatory diseases, tubular injury is secondary to glomerular lesions. In both of the latter groups of diseases, the progression starts in the glomerulus with the loss of the separation between the tuft and Bowman's capsule by forming cell bridges (parietal cells and/or podocytes) between the glomerular and the parietal basement membranes. Cell bridges develop into tuft adhesions to Bowman's capsule, which initiate the formation of crescents, either by misdirected filtration (proteinaceous crescents) or by epithelial cell proliferation (cellular crescents). Crescents may spread over the entire circumference of the glomerulus and, via the glomerulotubular junction, may extend onto the tubule. Two mechanisms concerning the transfer of a glomerular injury onto the tubulointerstitium are discussed: (1) direct encroachment of extracapillary lesions and (2) protein leakage into tubular urine, resulting in injury to the tubule and the interstitium. There is evidence that direct encroachment is the crucial mechanism. Progression of chronic renal disease is underlain by a vicious cycle which passes on the damage from lost and/or damaged nephrons to so far healthy nephrons. Presently, two mechanisms are discussed: (1) the loss of nephrons leads to compensatory mechanisms in the remaining nephrons (glomerular hypertension, hyperfiltration, hypertrophy) which increase their vulnerability to any further challenge (overload hypothesis); and (2) a proteinuric glomerular disease leads, by some way or another, to tubulointerstitial inflammation and fibrosis, accounting for the further deterioration of renal function (fibrosis hypothesis). So far, no convincing evidence has been published that in primary glomerular diseases fibrosis is harmful to healthy nephrons. The potential of glomerular injuries to regenerate or to be repaired by scaring is limited. The only option for extracapillary injuries with tuft adhesion is repair by formation of a segmental adherent scar (i.e., segmental glomerulosclerosis).